Effector memory T cells (T_EM) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (T_N) or memory (T_M) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an established method to convert TCR Tg cells to T_M and tested these for GVHD induction. This allowed us to control for the potentially different frequencies of alloreactive T cells among T_N and T_M, and to track fates of alloreactive T cells after transplantation. T_EM caused minimal, transient GVHD whereas central memory T cells (T_CM) caused potent GVHD. Surprisingly, T_EM were not inert: they, engrafted, homed to target tissues, and proliferated extensively, but they produced less IFN-γ and their expansion in target tissues was limited at later time points, and local proliferation was reduced. Thus, cell-intrinsic properties independent of repertoire explain the impairment of T_EM, which can initiate but cannot sustain expansion and tissue damage.